Cell cultures from the fetal mammalian central nervous system were used to study the neuronal death associated with Acquired Immune Deficiency Syndrome (AIDS). Purified envelope protein (qp120) from the AIDS virus was found to produce significant decreases in the number of surviving neurons in developing cultures derived from the spinal cord and hippocampus of the fetal mouse. Two characteristics of this toxicity were of particular interest. Gp120 produced neuronal deficits at extraordinarily low concentrations: 10-14 M. Secondly, an attenuation of the neuron-depleting effects of gp120 were observed at concentrations greater than 10-11 M. Using dissociated hippocampal cultures as a model system, several substances were investigated for their effect on gp120-induced neuronal death. D-Ala-Peptide T-amide prevented gp120-related death in a dose-dependent manner. No apparent neuronal death was observed with the addition of 10-10 M D-Ala-Peptide T-amide to gp120-treated test cultures. Vasoactive intestinal peptide, which contains a amino acid sequence similar to Peptide T, also prevented gp120-induced death at low (0.1 nM) concentrations.